Towards Product Control by Design: Studies of the Nucleation and Crystal Growth of L-Histidine

Aims:
To determine, using the latest generation of experimental techniques, the structural basis for the nucleation and growth behaviour of L-histidine, specifically metastable zone, facet-specific interactions and surface-solvent interactions, and relate this to variations in the product properties.

Objectives:
Establish the molecular basis for nucleation and crystal growth of Form A from water and Form B by crystallisation in the presence of ethanol.
Determine how solvent choice changes the polymorphic outcome
Understand the effects of pH and the zwitterionic effect on polymorphism and morphology.
Investigate the mechanistic basis for additive use (eg. amino acids and ionic species).

Methodology Proposed for the Proposed Project:
Studies will focus on the cooling and anti-solvent crystallisation of L-histidine from solution, in jacketed vessel reactors, and analysis of the crystallisation products. L-histidine was chosen because it is an industrially relevant product that is conformationally more complex than previously studies systems, but with individual functional groups for which previous studies have established deep molecular level understanding.

It has been recognised for decades that our lack of understanding the molecular basis for nucleation and crystal growth processes is a fundamental obstacle to predictive design of crystallisation processes and tailoring of product properties. Current design and control methods are based on classical nucleation theory (CNT), which does not take account of the molecular structure of solutions and the role of interfacial processes at the molecular level. It is widely recognised that progress towards predictive design of processes and products relies on establishing the relevant molecular transformations taking place and development of alternative models to CNT. The new suite of X-ray techniques applied in this project establishes for a first time a realistic perspective to achieve this. The impact would be transformational, in both academic and industrial research.

L-histidine is an essential amino acid used in a variety of industrial settings, such as pharmaceuticals, cosmetics, peptide therapeutics and as synthetic building blocks. Its crystal structure at microscopic level is fundamental to its industrial purpose, and fine-tuning crystallisation parameters can greatly affect characteristics of the final product, such as its longevity, stability, and how its morphology is optimised for purpose. A key feature in L-histidine's chemical structure is its imidazole side-chain, which is present in many industrial products such as fungicides, whilst also playing a crucial role in the binding of oxygen to haemoglobin in the bloodstream. As aromatic rings can play crucial roles in crystal formation and the intermolecular interactions that stabilise them, investigating the imidazole functionality as part of L-histidine can benefit research focussing on the fine structures of products containing imidazole functional groups as well as any imidazole-containing derivatives.

In addition to established analytical techniques for monitoring crystallisations (FTIR, Raman, XRD, NMR, UV-vis, DSC, TGA, XCT, etc.) a recently established new suite of X-ray techniques sensitive to molecular structure will be applied to determine the dynamic structure changes in solution during crystallisation, and of the characterise interfaces in the obtained products crystallisation behaviour, both in-situ and for isolated crystals in the solid state. These include X-ray pair distribution functions (XPDFs) alanysed by empirical potential structure refinement (EPSR), phase contrast XCT, X-ray Raman Scattering (XRS), and near-ambient pressure (NAP) XPS. Surface and interface analysis will be performed with XPS, NEXAFS and ToF-SIMS.

The CDT in Molecules to Product has the potential to make a real impact as a consequence of the transformative nature of the underpinning 'design and supply' paradigm. Through the exploitation of the generated scientific knowledge, a new approach to the product development lifecycle will be developed. This know-how will impact significantly on productivity, consistency and performance within the speciality chemicals, home and personal care (HPC), fast moving consumer goods (FMCG), food and beverage, and pharma/biopharma sectors.
UK manufacturing is facing a major challenge from competitor countries such as China that are not constrained by fixed manufacturing assets, consequently they can make products more efficiently and at significantly lower operational costs. For example, the biggest competition for some well recognised 'high-end' brands is from 'own-brand' products (simple formulations that are significantly cheaper). For UK companies to compete in the global market, there is a real need to differentiate themselves from the low-cost competition, hence the need for uncopiable or IP protected, enhanced product performance, higher productivity and greater consistency. The CDT is well placed to contribute to addressing this shift in focus though its research activities, with the PGR students serving as ambassadors for this change. The CDT will thus contribute to the sustainability of UK manufacturing and economic prosperity.
The route to ensuring industry will benefit from the 'paradigm' is through the PGR students who will be highly employable as a result of their unique skills-set. This is a result of the CDT research and training programme addressing a major gap identified by industry during the co-creation of the CDT. Resulting absorptive capacity is thus significant. In addition to their core skills, the PGR students will learn new ones enabling them to work across disciplinary boundaries with a detailed understanding of the chemicals-continuum. Importantly, they will also be trained in innovation and enterprise enabling them to challenge the current status quo of 'development and manufacture' and become future leaders.
The outputs of the research projects will be collated into a structured database. This will significantly increase the impact and reach of the research, as well as ensuring the CDT outputs have a long-term transformative effect. Through this route, the industrial partners will benefit from the knowledge generated from across the totality of the product development lifecycle. The database will additionally provide the foundations from which 'benchmark processes' are tackled demonstrating the benefits of the new approach to transitioning from molecules to product.
The impact of the CDT training will be significantly wider than the CDT itself. By offering modules as Continuing Professional Development courses to industry, current employees in chemical-related sectors will have the opportunity to up-skill in new and emerging areas. The modules will also be made available to other CDTs, will serve as part of company graduate programmes and contribute to further learning opportunities for those seeking professional accreditation as Chartered Chemical Engineers.
The CDT, through public engagement activities, will serve as a platform to raise awareness of the scientific and technical challenges that underpin many of the items they rely on in daily life. For example, fast moving consumer goods including laundry products, toiletries, greener herbicides, over-the-counter drugs and processed foods. Activities will include public debates and local and national STEM events. All events will have two-way engagement to encourage the general public to think what the research could mean for them. Additionally these activities will provide the opportunity to dispel the myths around STEM in terms of career opportunities and to promote it as an activity to be embraced by all thereby contributing to the ED&I agenda.